The present invention relates to stable crystals of acid addition salts of optically active thienotriazolodiazepine compounds, which have antagonistic activity on platelet-activating factor and are useful as pharmaceuticals.
Ever since Benbeniste et al found a factor capable of strongly aggregating platelets [platelet-activating factor (PAF)] from rabbit basocytes in 1972, the physiological roles of PAF have been investigated, and it has been clarified that PAF is a factor for various physiological reactions including platelet aggregation, hypotension, acute allergy, smooth muscle contraction, inflammation, pain, edema, as well as disorders in respiratory, cardio-vascular and venous systems in living bodies.
Accordingly, a compound having PAF-antagonistic activity is considered to be extremely useful for various PAF-induced diseases including inflammations, allergies, anaphylactic shocks, septic shocks, vascular diseases such as DIC (disseminated intravascular coagulation), myocardinal diseases, asthma, pulmonary edema, and adult respiratory diseases, and many studies of substances having antagonistic action against physiological activity of PAF have been under way.
The present inventors invented compounds having extremely strong PAF-antagonistic activity; for example, (.+-.)-4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-th ieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (hereinafter referred to as Compound A, U.S. Pat. No. 4,820,703) of the following formula ##STR2## and (.+-.)-3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[ 4,3-a][1,4]diazepin-2-yl]propionic acid morpholide (hereinafter referred to as Compound B, U.S. Pat. No. 4,937,240) of the following formula ##STR3##
These Compounds A and B possess strong PAF-antagonistic activity and are useful as PAF-antagonists. These Compounds have an asymmetric carbon at the 6-position, and an isomer whose absolute configuration is an S-configuration has several times stronger PAF-antagonistic activity than Compounds A and B (racemates), and is low toxic with less effect on the central nervous system. Furthermore, since the isomer is effective by oral administration and long-lasting, it is more useful as a pharmaceutical.
However, these optically active isomers of Compound A and Compound B, having an S-configuration could be obtained only as an amorphous by a conventional purification method (e.g. column chromatography, recrystallization), and large-scale synthesis and purification thereof have been extremely difficult, causing many problems in terms of purification and physico-chemical properties which are important for medicinal standardization and pharmaceutical formulation. Thus, obtaining them as stable crystals has been the major object in developing them as pharmaceuticals.